The role of chloride, as distinct from sodium, in the body's electrolyte, fluid and acid base economy continues to be the major focus of these proposals. Chloride depletion in man is common, mainly secondary to loss of gastric chloride, respiratory acidosis, and loop diuretics. Within the nephron numerous specific transport mechanisms underlying chloride absorption, especially in the distal nephron, have been recently elucidated. Chloride delivery to or reabsorption in various nephron segments importantly influences renal renin release, tubuloglomerular feedback control of glomerular filtration rate, bicarbonate reabsorption, renal concentration and dilution, and potassium conservation and excretion. Chloride transport mechanisms may be influenced by autocoids, antidiuretic hormone, adrenal hormones and the sympathetic nervous system. It is proposed to examine simultaneously chloride and bicarbonate reabsorption in chronic metabolic alkalosis and in chronic respiratory acidosis, two acid-base disturbances in which the kidney is challenged by the problem of maintaining extracellular fluid volume despite chronic hypochloremia and hyperbicarbonatemia. Methods used will include metabolic balance, clearance, and various single nephron micropuncture, microperfusion and microinjection techniques in an effort to integrate systemic, renal and single nephron responses. A new hypothesis arising from animal studies whereby chloride depletion per se can sustain renal maintenance of a high plasma bicarbonate in chloride deletion alkalosis is to be tested experimentally in normal man. Additional studies are designed to characterize important physiological and pathophysiological influences on chloride reabsorption in the loop segment and, specifically, in the "diluting segment", the thick ascending limb of the loop of Henle. The ultimate goal of these studies is a better understanding of these important perturbations of acid-base, fluid and electrolyte balance in man.